We have previously established that endothelin-1 (ET-1) induces receptor (ET/A) mediated cerebromicrovascular permeability changes and may function on a proinflammatory agent. Lately, we have also demonstrated that ET-1 and ET-3 modulates the ion transport systems (Na+-K+-ATPase and Na+/K+/Cl--cotransport) in endothelial cells derived from capillaries of rat brain. The experiments described here examined the effect of endothelin (ET-1) on another ion transport pathway, namely sodium/hydrogen (Na+/H+ exchange system) in rat brain capillary endothelium (RBEC). ET-1, ET-2 and ET-3 stimulated Na+ uptake into REBC with similar half- maximal stimulation (EC50 ) values (0.7, 0.6, and 1.1 nM, respectively). This reaction was inhibited by the Na+ /H+ antiport inhibitor, N-(ethyl- N-isopropyl)-amiloride (EIPA). The selective endothelin A (ET/A ) receptor-antagonist [Cyclo-D-Trp-D-Asp-Pro-D-Val-Leu BQ123], but not endothelin B (ET/B) receptor-antagonists[(Cys11, Cys15)-ET-1 (IRL1038) or N-cis-2,6-dimethylprperidinocarbonyl-L-gamma MeLeu-D-trp (COOMe)-D- Nle-ONa (BQ788)], inhibited both ET-1 and ET-3 stimulated Na+ receptor mediation. The protein kinase C (PKC) activator [phorbol 12-myristate 13-acetate (MAO) failed to stimulate Na+uptake. The calcium-calmodulin (CaM) inhibitor (W7) reduced ET-1 stimulate Na+uptake by 50%, whereas the PKC inhibitor (staurosporine) had no effect, indicating that ET-1 stimulation of Na+ /H+ antiport system is linked to a CaM-dependent and PKC-independent pathway. The present results further support the idea that endothelins play a role in regulating ion transport across the blood-brain barrier..